Spray drying method of semeglutide

Abstract

The invention provides a spray drying method of a semeglutide solution, which is characterized in that the semeglutide solution and drying gas are simultaneously introduced into a spray dryer, the ratio of the airflow velocity (kg / h) of the drying gas to the feeding flow velocity (kg / h) of the semeglutide solution is (120-900): 1, and the air inlet temperature of the drying gas is 40-60 DEG C. The spray drying method disclosed by the invention is high in production efficiency and short in production time, and meanwhile, the yield and the product quality can be kept unchanged.

Description

TECHNICAL FIELD

[0001] The present invention belongs to the field of spray drying, more specifically, to a method for spray drying of a semaglutide solution. BACKGROUND

[0002] Semaglutide is a long-acting glucagon-like peptide-1 receptor agonist developed by Novo Nordisk, which has 94% structural homology with natural GLP-1. It is a peptide substance composed of a 31-amino acid peptide backbone and a fatty acid side chain. Based on natural GLP-1, the alpha-amino isobutyric acid at position 8 of semaglutide replaces alanine, increasing resistance to dipeptidyl peptidase-4 (DPP-4) degradation. The lysine at position 26 is connected to a C-18 fatty diacid side chain with glutamic acid as a spacer, increasing the affinity for proteins, avoiding rapid clearance of the drug by the kidneys, and prolonging the half-life of the drug. The arginine at position 34 replaces lysine, preventing the misplacement of the C-18 fatty acid chain, increasing the stability of the side chain. Semaglutide stimulates pancreatic beta cells to secrete insulin and inhibits pancreatic alpha cells to secrete glucagon, thereby reducing fasting and postprandial blood glucose. Semaglutide can also act on the digestive tract to delay gastric emptying and increase satiety. In addition, GLP-1RA can act on the brain to suppress appetite and on the cardiovascular system to repair damaged endothelium and improve endothelial function.

[0003] Semaglutide is a peptide drug with high polarity and hydrophilicity, and its solubility is poor in organic solvents and good in water. Therefore, semaglutide is usually obtained by lyophilization or spray drying. Lyophilization has the disadvantages of complex process, long production cycle, high cost, and poor flowability of the product. Spray drying has the advantages of simple process, short production cycle, low cost, and good flowability of the product with a spherical appearance.

[0004] Production cost is a factor that must be considered in drug production. For the spray drying step of semaglutide, reducing production cost can be approached from the following two aspects: 1) improving yield (during the spray drying process of the drug substance, the product will inevitably be lost, such as adhering to the wall of the spray dryer); 2) improving production efficiency and shortening production time.

[0005] Spray drying involves the following parameters:

[0006] Centrifugal frequency: proportional to centrifugal speed, the higher the frequency, the faster the speed. The main function is to change the liquid into small droplets. The larger the speed, the smaller the droplets, which are easier to dry. However, the larger the speed, the greater the centrifugal force, which causes the droplets to be easily thrown to the wall of the drying tower, thereby affecting the yield.

[0007] Dry gas flow rate (inlet air volume): The main function is to carry away the solvent and dry the product. The greater the flow rate, the higher the drying efficiency, but too large a flow rate will have a negative effect on product yield.

[0008] Atomizing gas flow rate: The main function is to disperse the liquid material into small droplets. Generally, the nozzle aperture is a fixed value, and the flow rate is reflected by the pressure. The greater the flow rate, the greater the pressure, and the smaller the diameter of the dispersed droplets.

[0009] Feed flow rate: The flow rate of the solution entering the drying tower. The greater the flow rate, the higher the production efficiency, but too large a flow rate may not dry completely.

[0010] Inlet air temperature: The temperature of the heated drying gas entering the drying tower. The higher the temperature, the higher the drying efficiency, but too high a temperature may cause product damage.

[0011] Outlet air temperature: The temperature of the hot gas leaving the drying tower. The outlet air temperature reflects the energy utilization efficiency of the drying process. Too high a temperature may indicate waste of heat, and too low a temperature may indicate insufficient drying.

[0012] Inlet air dew point: Represents the water content of the drying gas. The lower the dew point, the smaller the water content, and the higher the drying efficiency.

[0013] Prior art CN113194929A discloses a spray drying process for semeglutide, the main technical feature of which is to control the ratio of atomizing gas flow rate to semeglutide solution feed flow rate (1:1.0-1.7) to improve product yield and reduce production cost. This prior art does not address how to improve production efficiency and shorten production time.

[0014] According to conventional theory, there are two ways to improve production efficiency: 1) increase the feed rate; 2) increase the solution concentration. However, in actual spray drying processes, due to the influence of various parameters, it is difficult to achieve both methods simultaneously. For example, regarding increasing the feed rate, the existing technology CN113194929A requires both increasing the feed flow rate and providing an atomizing gas flow rate (maintaining the ratio of the atomizing gas flow rate to the feed flow rate) to atomize the solution into smaller droplets, thereby obtaining a product with a smaller particle size. Smaller particle sizes have lower density and are more easily carried away by the drying gas and the solvent within them by the atomizing gas, but this increases the difficulty of collection and consequently reduces the yield. As for increasing the solution concentration, generally, increasing the solution concentration leads to increased viscosity, resulting in incomplete drying of the product (high moisture content), which in turn affects product quality. This is why the highest concentration of the semaglutide solution disclosed in the embodiments of prior art CN113194929A is approximately 5%, while the concentrations of the semaglutide solutions claimed in its claims are 0.5-10%, 1-5%, and 1-3%. This indicates that further increasing the solution concentration to obtain a satisfactory product through spray drying presents a significant challenge. Consequently, most existing spray drying processes suffer from low production efficiency. Summary of the Invention

[0015] To address the problems existing in the spray drying of semaglutide solution in the prior art, this invention provides a highly efficient spray drying method for producing semaglutide pharmaceutical raw material. In the spray drying method of this invention, the semaglutide solution and the drying gas are simultaneously introduced into the spray dryer, and the flow rate of the drying gas (m...) 3 The ratio of the feed flow rate (kg / h) of the dry gas to the feed flow rate (kg / h) of the smegglutinin solution is 120–900:1, and the inlet temperature of the dry gas is 40–60°C.

[0016] In some other preferred embodiments of the invention, the airflow velocity (m) of the drying gas is... 3 The ratio of the feed flow rate (kg / h) of the feed to the megglutinin solution is 150–400:1, more preferably 200–300:1.

[0017] In some other preferred embodiments of the present invention, the mass concentration of the smegglutinin solution is 0.5-25%, more preferably 5-20%.

[0018] In some other preferred embodiments of the present invention, the solvent for the smegglutinin solution is purified water.

[0019] In some other preferred embodiments of the present invention, the feed flow rate of the megglutinin solution is 0.5 to 7 kg / h, more preferably 3 to 5 kg / h.

[0020] In some other preferred embodiments of the invention, the drying gas is air.

[0021] In some other preferred embodiments of the present invention, the drying gas flow rate is 400–1500 m / s. 3 / h, preferably 500-1200m 3 / h.

[0022] In some other preferred embodiments of the present invention, the outlet temperature of the drying gas is 28–50°C.

[0023] In some other preferred embodiments of the present invention, the dew point of the dry gas supply is -50°C to -10°C.

[0024] In some other preferred embodiments of the present invention, the smegglutinin solution is atomized by centrifugal atomization.

[0025] In some other preferred embodiments of the present invention, the centrifugation of the centrifugal atomization is at a frequency of 200-600 Hz, more preferably 300-500 Hz.

[0026] In some other preferred embodiments of the present invention, in the spray drying method of the smegglutinin aqueous solution, the smegglutinin aqueous solution with a mass concentration of 0.5-25% is introduced into the spray dryer at a feed flow rate of 1-5 kg / h, atomized by centrifugal atomization, and air is used as the drying gas at a flow rate of 400-1500 m. 3 The gas is introduced into the spray dryer at a flow rate of / h, with an inlet temperature of 40-60℃ and an outlet temperature of 28-50℃. Attached Figure Description

[0027] Figure 1 This is a dot plot of the ratio of the atomized gas flow rate to the feed flow rate of the smegglutinin solution obtained in Example 1 to the product yield.

[0028] Figure 2 This is a dot plot of the ratio of the atomized gas flow rate to the feed flow rate of the smegglutinin solution obtained in Example 1 to the product water content. Detailed Implementation

[0029] In the process of preparing semaglutide formulations, the inventors of this application discovered that existing spray drying methods for preparing semaglutide granules suffer from low production efficiency. For example, the concentration of the semaglutide solution in the feed is low, or the feed rate is slow. Furthermore, existing spray drying methods for semaglutide require the use of organic solvents to prepare the semaglutide solution. Through in-depth research, the inventors of this application unexpectedly discovered that in the process of spray drying semaglutide granules, the ratio between the airflow rate of the drying gas and the feed flow rate of the semaglutide solution has a particularly significant impact on the production efficiency of obtaining semaglutide granules through spray drying. Within a specific range of the ratio between the airflow rate of the drying gas and the feed flow rate of the semaglutide solution, a higher concentration of semaglutide aqueous solution can be used for spray drying, and the yield and water content of the obtained product meet the requirements.

[0030] Spray drying method of semaglutide solution

[0031] In the spray drying method for smegglutinin solution provided by this invention, the airflow velocity (m) of the drying gas is... 3 The ratio of the feed flow rate (kg / h) of the dry gas to the feed flow rate (kg / h) of the smegglutinin solution is 120–900:1, and the inlet temperature of the dry gas is 40–60°C.

[0032] In the spray drying method for the smegglutinin solution of the present invention, the atomization method used is centrifugal spraying. Compared with gas atomization, centrifugal atomization produces larger droplets, resulting in larger sample particle size after drying, less adhesion to the inner wall of the drying pan, and higher yield.

[0033] In the spray drying method for the smegglutinin solution of the present invention, purified water is used as the solvent, and no organic solvents, such as ethanol, are used. This reduces both costs and environmental pollution. "Purified water" refers to distilled water or deionized water.

[0034] In the spray drying method for the smegglutinin solution of the present invention, air is used as the drying gas, and the air requires no pre- or post-treatment. This further reduces production costs.

[0035] In the spray drying method for the semaglutide solution of the present invention, the outlet temperature of the drying gas is 28–50°C. Both the inlet and outlet temperatures of this drying gas are relatively low, avoiding the generation of impurities in the semaglutide due to excessively high temperatures.

[0036] The spray drying method for semaglutide solution of the present invention can process high concentration (5-20%) semaglutide solution, thereby improving production efficiency and reducing production costs.

[0037] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0038] 1. Airflow velocity of the dry gas (m) 3 When the ratio of feed flow rate (kg / h) to smegglutinin solution is 120–900, production efficiency can be improved and production time shortened by increasing the concentration of smegglutinin solution, while maintaining yield and product quality.

[0039] 2. Water is used as the solvent, eliminating the need for organic solvents and causing no environmental pollution.

[0040] 3. The drying medium is air, which poses a low safety risk.

[0041] 4. The outlet and inlet temperatures of the drying gas are both low, resulting in stable product quality.

[0042] The present invention will be further illustrated below with reference to specific embodiments. It should be understood that these embodiments are for illustrative purposes only and are not intended to limit the scope of the invention. Experimental methods in the following embodiments that do not specify specific conditions are generally performed under conventional conditions. Unless otherwise stated, percentages and concentrations are weight percentages and mass concentrations. Reagents or raw materials used in the following embodiments, unless otherwise stated, are generally commercially available or can be prepared according to methods disclosed in the prior art.

[0043] Comparative Example 1

[0044] A 55% (w / w) aqueous solution of semaglutide in ethanol was spray-dried using a Büchi B290-295 spray dryer. Nitrogen was used as both the atomizing and drying gas. The nozzle diameter was 0.7 mm, and the condenser temperature setpoint was 5 °C. The suction pump was started at 100% capacity, with a nitrogen flow rate of 0.3-1.0 kg / h. Heating was initiated, and when the outlet air temperature reached 55-90 °C, the peristaltic pump was activated at a feed rate of 0.3-0.5 kg / h. The outlet air temperature was controlled by adjusting the inlet air temperature to achieve the preset target value. After spray drying, samples were collected, the yield was calculated, and the water content of the samples was determined. The spray drying parameters and results are shown in Table 1.

[0045] Table 1

[0046]

[0047] Note: In Table 1, the target yield is ≥80%, and the water content limit is ≤10.0%.

[0048] The results in Table 1 show that: 1) When the ratio of atomizing gas flow rate to semaglutide solution feed rate remains constant, increasing both the atomizing gas flow rate and the semaglutide solution feed rate tends to decrease the product yield. When both the atomizing gas flow rate and the semaglutide solution feed rate are increased to three times their original values, the product yield is below 80%. 2) Increasing the concentration of the semaglutide solution tends to increase the water content of the resulting product.

[0049] Example 1:

[0050] Smegglutide aqueous solution was spray-dried using a spray dryer (Shanghai Qiaofeng, QFN-DW-5). Air was used as the drying gas. The centrifugation frequency was 300 Hz, and the chilled water temperature was 5-10℃. The inlet temperature of the drying gas was set to ≤60℃. The equipment was turned on, and when the outlet temperature of the drying gas reached the target value, the peristaltic pump was started. The outlet temperature of the drying gas was controlled by fine-tuning the inlet temperature to achieve the preset target value. After spray drying, samples were collected and the yield was calculated. The water content in the samples was also measured. Spray drying parameters and results are shown in Table 2.

[0051] Table 2

[0052]

[0053]

[0054] Note: In Table 2, the target yield is ≥80%; the water content limit is ≤10.0%.

[0055] The results in Table 2 show that: 1) When the airflow velocity (m) of the dry gas... 3 When the feed flow rate (kg / h) of the smegglutinin aqueous solution is approximately 120–900:1, the concentration of the smegglutinin solution has no significant effect on the yield and water content of the spray-dried product. Therefore, the concentration of the smegglutinin solution can be increased to 2–4 times the original concentration, and the production efficiency will increase by the same factor, without affecting the product yield and product quality (water content). 2) When the airflow velocity (m... 3 When the ratio of the feed flow rate (kg / h) of the drying gas to that of the smegglutinin solution is greater than 900:1, the product yield is significantly affected. This may be because the excessive flow rate of the drying gas causes more product to be blown away, making collection impossible or difficult. 3) When the airflow velocity (m) 3 When the ratio of the feed flow rate (kg / h) of the product to that of the smegglutinin solution is less than 120:1, the product water content increases significantly, making it impossible to dry completely.

[0056] Will Figure 1Plot the ratio of airflow velocity to feed flow rate of smegglutide solution against product yield and product moisture content.

[0057] Example 2

[0058] Smegglutide aqueous solution was spray-dried using a spray dryer (Shanghai Qiaofeng, QFN-DW-5). Air was used as the drying gas. The chilled water temperature was 5-10℃. The inlet temperature of the drying gas was set to 50℃, and the centrifugal atomization frequency was set to 400Hz. The equipment was turned on, and when the outlet temperature of the drying gas reached the target value, the peristaltic pump was activated. The outlet temperature of the drying gas was controlled by fine-tuning the inlet temperature to achieve the preset target value. After spray drying, samples were collected and the yield was calculated. The water content of the samples was also measured. Spray drying parameters and results are shown in Table 3.

[0059] Table 3

[0060]

[0061] Note: In Table 3, the target yield is ≥80%; the water content limit is ≤10.0%.

[0062] Table 3 shows that the technology of this invention can produce 0.842 kg of qualified products per hour.

[0063] Example 3

[0064] The aqueous solution of smegglutide was spray-dried using a spray dryer (Shanghai Qiaofeng, QFN-DW-5). Air was used as the drying gas. The chilled water temperature was 5-10℃. The inlet temperature of the drying gas was set to 55℃, and the centrifugal atomization frequency was set to 400Hz. The equipment was turned on, and when the outlet temperature of the drying gas reached the target value, the peristaltic pump was activated. The outlet temperature of the drying gas was controlled by fine-tuning the inlet temperature to achieve the preset target value. After spray drying, the sample was collected, the yield was calculated, and the water content of the sample was measured. The spray drying parameters and results are shown in Table 3.

[0065] Table 4

[0066]

[0067] Note: In Table 4, the target yield is ≥80%; the water content limit is ≤10.0%.

[0068] Table 4 shows that the spray drying method of the present invention can produce 0.525 kg of qualified smegglutinin per hour.

[0069] Furthermore, it should be understood that after reading the above teachings of this invention, those skilled in the art can make various alterations or modifications to this invention, and these equivalent forms also fall within the scope defined by the appended claims.

Claims

1. A spray drying method for a semaglutide solution, wherein the semaglutide solution and a drying gas are simultaneously introduced into a spray dryer, characterized in that, The airflow velocity of the dry gas, in meters. 3 The feed flow rate of the smegglutinin solution is kg / h, the ratio is 120-900:1, and the inlet temperature of the drying gas is 40-60℃.

2. The spray drying method according to claim 1, characterized in that, The airflow velocity of the dry gas, in meters. 3 The feed flow rate of the megglutinin solution, kg / h, is 150–400:1, more preferably 200–300:

1.

3. The spray drying method according to claim 1, characterized in that, The mass concentration of the smegglutinin solution is 0.5-25%, more preferably 5-20%.

4. The spray drying method according to claim 1, characterized in that, The solvent for the smegglutinin solution is purified water.

5. The spray drying method according to claim 1, characterized in that, The feed flow rate of the megglutinin solution is 0.5-7 kg / h, preferably 3-5 kg / h.

6. The spray drying method according to claim 1, characterized in that, The drying gas is air.

7. The spray drying method according to claim 1, characterized in that, The airflow velocity of the drying gas is 400–1500 m / s. 3 / h, preferably 500-1200m 3 / h.

8. The spray drying method according to claim 1, characterized in that, The outlet temperature of the drying gas is 28–50°C, and / or The dew point of the dry gas supply is -50℃ to -10℃.

9. The spray drying method according to claim 1, characterized in that, The nebulization method for the smegglutinin solution is centrifugal nebulization. Preferably, the centrifugation frequency is 200-600Hz, more preferably 300-500Hz.

10. A spray drying method for an aqueous solution of smegglutinin, characterized in that, A 0.5–25% (w / w) aqueous solution of smegglutinin is introduced into a spray dryer at a feed flow rate of 1–5 kg / h, and atomized using centrifugal atomization with air as the drying gas at a flow rate of 400–1500 m³ / h. 3 An airflow velocity of / h is introduced into the spray dryer, with an inlet temperature of 40-60℃ and an outlet temperature of 28-50℃.

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